Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression
Hyangin Kim, … , Yinghong Tian, Jianren Mao
Hyangin Kim, … , Yinghong Tian, Jianren Mao
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(8):2940-2954. https://doi.org/10.1172/JCI61884.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 7

Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression

Abstract

Pain and depression are frequently comorbid disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in this comorbidity. We found that chronic pain in rats induced depressive behavior and IDO1 upregulation in the bilateral hippocampus. Upregulation of IDO1 resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. We observed elevated plasma IDO activity in patients with both pain and depression, as well as in rats with anhedonia induced by chronic social stress. Intra-hippocampal administration of IL-6 in rats, in addition to in vitro experiments, demonstrated that IL-6 induces IDO1 expression through the JAK/STAT pathway. Further, either Ido1 gene knockout or pharmacological inhibition of hippocampal IDO1 activity attenuated both nociceptive and depressive behavior. These results reveal an IDO1-mediated regulatory mechanism underlying the comorbidity of pain and depression and suggest a new strategy for the concurrent treatment of both conditions via modulation of brain IDO1 activity.

Authors

Hyangin Kim, Lucy Chen, Grewo Lim, Backil Sung, Shuxing Wang, Michael F. McCabe, Gabriel Rusanescu, Liling Yang, Yinghong Tian, Jianren Mao

×

Figure 7

Role of IL-6 in the hippocampal JAK/STAT pathway.

Options: View larger image (or click on image) Download as PowerPoint
Role of IL-6 in the hippocampal JAK/STAT pathway. (A and B) The plasma I...
(A and B) The plasma IL-6 concentration was increased (A, ELISA), as was Il6 mRNA expression in the hippocampus (B, real-time PCR), in rats with CFA-induced arthritis. (C) Il6 mRNA expression was also increased in the hippocampus of both IDO-knockout and wild-type mice with CFA-induced arthritis. Mean ± SEM, n = 6, *P < 0.05 compared with sham control. (D) The plasma IL-6 level was elevated in patients with both chronic back pain and depression (ELISA). Mean ± SEM, n = 13–20, *P < 0.05 compared with healthy control. (E–G) The expression of JAK2 (E), STAT3 (F), and p-STAT3 (G) in the hippocampus was increased in rats with CFA-induced arthritis (Western blot analysis). C-1, C-7, and C-14, samples taken on days 1, 7, and 14 from rats with CFA-induced arthritis; S-1, S-7, and S-14, samples taken on days 1, 7, and 14 from sham control rats. β-Actin was used as loading control. Mean ± SEM, n = 4–5, *P < 0.05 compared with sham control.